Expanding the Clinical Utility of Targeted RNA Sequencing Panels beyond Gene Fusions to Complex, Intragenic Structural Rearrangements.

Gene fusions are a form of structural rearrangement well established as driver events in pediatric and adult cancers. The identification of such events holds clinical significance in the refinement, prognostication, and provision of treatment in cancer. Structural rearrangements also extend beyond fusions to include intragenic rearrangements, such as internal tandem duplications (ITDs) or exon-level deletions. These intragenic events have been increasingly implicated as cancer-promoting events. However, the detection of intragenic rearrangements may be challenging to resolve bioinformatically with short-read sequencing technologies and therefore may not be routinely assessed in panel-based testing. Within an academic clinical laboratory, over three years, a total of 608 disease-involved samples (522 hematologic malignancy, 86 solid tumors) underwent clinical testing using Anchored Multiplex PCR (AMP)-based RNA sequencing. Hematologic malignancies were evaluated using a custom Pan-Heme 154 gene panel, while solid tumors were assessed using a custom Pan-Solid 115 gene panel. Gene fusions, ITDs, and intragenic deletions were assessed for diagnostic, prognostic, or therapeutic significance. When considering gene fusions alone, we report an overall diagnostic yield of 36% (37% hematologic malignancy, 41% solid tumors). When including intragenic structural rearrangements, the overall diagnostic yield increased to 48% (48% hematologic malignancy, 45% solid tumor). We demonstrate the clinical utility of reporting structural rearrangements, including gene fusions and intragenic structural rearrangements, using an AMP-based RNA sequencing panel.

Exploring the utility of current polygenic scores in capturing resilience.

Although resilience has been identified to be moderately heritable, little is known about the genetic variants involved. While there has not yet been a robust genome-wide association study (GWAS) of resilience, existing GWAS of related phenotypes may provide a starting point for developing our understanding of the heritability of resilience. In a sample of older, US adults (N = 9480), we examined the extent to which proxy polygenic scores (PGS) explained the variance in resilience. Four of the 32 PGS assessed (subjective wellbeing, neuroticism, depressive symptoms and educational attainment) reached significance among participants with European ancestries, but with relatively small effects (= 0.002-0.09). Notably, PGSs derived from GWAS of PTSD among participants with either European or African ancestries were uncorrelated with resilience. Even aggregated across all available proxy PGSs, existing PGSs are not sufficient to inform our understanding of the genetics underlying the heritability of resilience. A large-scale GWAS of resilience is needed as it would provide greater insight into the genetic mechanisms underlying the heritability of resilience.